title: Increasing cGMP-dependent protein kinase I activity attenuates cisplatin-induced kidney injury through protection of mitochondria function.
abstract: Cisplatin is widely used to treat malignancies. However, its major limitation is the development of dose-dependent nephrotoxicity. The precise mechanisms of cisplatin-induced kidney damage remain unclear, and the renoprotective agents during cisplatin treatment are still lacking. Here, we demonstrated that the expression and activity of cGMP-dependent protein kinase-I (PKG-I) were reduced in cisplatin-treated renal tubular cells in vitro as well as in the kidney tissues from cisplatin-treated mice in vivo. Increasing PKG activity by both pharmacological and genetic approaches attenuated cisplatin-induced kidney cell apoptosis in vitro. This was accompanied by decreased Bax/Bcl2 ratio, caspase 3 activity, and cytochrome c release. Cisplatin-induced mitochondria membrane potential loss in the tubular cells was also prevented by increased PKG activity. All of these data suggest a protective effect of PKG on mitochondria function in renal tubular cells. Importantly, increasing PKG activity pharmacologically or genetically diminished cisplatin-induced tubular damage and preserved renal function during cisplatin treatment in vivo. Mitochondria structural and functional damage in the kidney from cisplatin-treated mice was inhibited by increased PKG activity. In addition, increasing PKG activity enhanced ciaplatin-induced cell death in several cancer cell lines. Taken together, these results suggest that increasing PKG activity may be a novel option for renoprotection during cisplatin-based chemotherapy.
authors.affiliation: Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg. Rm. 583, 900 S. Limestone St., Lexington, KY 40536. swang7@uky.edu.
authors.forename: Hasiyeti
authors.initials: H
authors.lastname: Maimaitiyiming
authors.forename: Yanzhang
authors.initials: Y
authors.lastname: Li
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Cui
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Tong
authors.forename: Heather
authors.initials: H
authors.lastname: Norman
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qi
authors.forename: Shuxia
authors.initials: S
authors.lastname: Wang
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*
chemical_list: D062965:Cyclic GMP-Dependent Protein Kinase Type I; D002945:Cisplatin
keywords: PKG-I; cisplatin; mitochondria; tubular cells